In the past, a Non-Steroidal Anti-Inflammatory Drug (hereinafter referred to as NSAID) has been known as an anti-inflammatory analgesic. The NSAID has an activity to control a production of prostaglandin relating to inflammatory and/or pain generation by inhibiting cyclooxygenase (hereinafter referred to as COX), which catalyzes the first reaction in the arachidonate cascade, a metabolic pathway to potentiate a pain.
However, serious side effects are sometimes reported when the production of prostaglandin is excessively controlled by administration of NSAID since prostaglandin has various effects other than inflammation or pain generation. For example, when COX activity is inhibited, a lipoxygenase activity is stimulated instead and increase of leukotriene reduces gastric secretion; simultaneously mucosa membrane of the digestive organ is damaged by increased active oxygen and ulcer is generated. Examples of other side effects include renal dysfunction, hepatic dysfunction, skin rush and the like, and especially induction of aspirin asthma is fatal among them.
Under this circumstance, a lot of efforts have been poured into developing external preparation of NSAID having less side effects. It would be possible to reduce systemic side effects and realize high drug level at an affected site by transdermal delivery of NSAID thereto.
Some NSAID, however, have quite limited transdermal permeability and the pharmaceutical effect when administered as an external formulation is dramatically reduced compared with those of an oral administration. In response, a composition of external anti-inflammatory analgesic comprising NSAID and a local anesthetic is proposed in order to improve the transdermal absorbability of NSAID (Patent Literature 1).
Patent Literature 2 also discloses a formulation comprising etodolac as NSAID and describes that the transdermal permeability of etodolac is improved when lidocaine is combined with etodolac. But, all that described therein is a broad range of incorporated lidocaine, which is 0.1 to 1.8 molar compared to 1 molar of etodolac, and effect of 1.2 molar of lidocaine combined with 1 molar of etodolac in test example 1. Characteristic transdermal permeability and/or tissue penetration ability of the present invention, which is a tape preparation comprising an ionic liquid of etodolac (ambient temperature molten salt with equimolar lidocaine), is therefore never disclosed.
Further Patent Literature 3 describes that a formation of ionic liquid enhances transdermal permeability of an agent, but it is not disclosed whether a usual formulation technique is applicable or not when an ionic liquid of the agent is formed, much less the appropriate formulation recipe was predicted regarding an ionic liquid of etodolac,
Patent Literature 1: JP2002-128699A
Patent Literature 2: JP2005-239709A
Patent Literature 1: JP2005-82512A